A B S T R A C T Germline mutations in SAMD9 and SAMD9L genes cause MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) (OMIM: *610456) and ataxia-pancytopenia (OMIM: *611170) syndromes, respectively, and are associated with chromosome 7 deletions, myelodysplastic syndrome (MDS), and bone marrow failure. In this retrospective series, we report outcomes of allogeneic hematopoietic cell transplantation (HCT) in patients with hematologic disorders associated with SAMD9/SAMD9L mutations. Twelve patients underwent allogeneic HCT for MDS (n = 10), congenital amegakaryocytic thrombocytopenia (n = 1), and dyskeratosis congenita (n = 1). Exome sequencing revealed heterozygous mutations in SAMD9 (n = 6) or SAMD9L (n = 6) genes. Four SAMD9 patients had features of MIRAGE syndrome. Median age at HCT was 2.8 years (range, 1.2 to 12.8 years). Conditioning was myeloablative in 9 cases and reduced intensity in 3 cases. Syndrome-related comorbidities (diarrhea, infections, adrenal insufficiency, malnutrition, and electrolyte imbalance) were present in MIRAGE syndrome cases. One patient with a familial SAMD9L mutation, MDS, and morbid obesity failed to engraft and died of refractory acute myeloid leukemia. The other 11 patients achieved neutrophil engraftment. Acute post-transplant course was complicated by syndrome-related comorbidities in MIRAGE cases. A patient with SAMD9L-associated MDS died of diffuse alveolar hemorrhage. The other 10 patients had resolution of hematologic disorder and sustained peripheral blood donor chimerism. Ten of 12 patients were alive with a median follow-up of 3.1 years (range, 0.1 to 14.7 years). More data are needed to refine transplant approaches in SAMD9/ SAMD9L patients with significant comorbidities and to develop guidelines for their long-term follow-up.

We present a comprehensive comparison of PAX5,IKZF1, and CDKN2A/B abnormalities in 21 B-cell precursor acute lymphoblastic leukemia (B-ALL) patients studied by aCGH and gene-specific FISH assays. In our cohort of B-ALL patients, alterations of IKZF1, PAX5, and CDKN2A/B were detected by aCGH analysis in 43, 52, and 57% of samples, respectively. Deletions of IKZF1 were present in 9 samples, including 5 cases positive for both PAX5 and IKZF1 deletions, implying digenic impairment. Furthermore, all cases with IKZF1 deletions also had additional genomic alterations, including BCR-ABL1 gene fusions, PAX5 deletions, CDKN2A/B deletions, and FLT3 amplification. Deletions of CDKN2A/B represented the most frequent abnormalities in our group of patients. Our study demonstrates the high incidence of PAX5, IKZF1, and CDKN2A/B alterations in B-ALL detected by aCGH analysis. Due to the small size and variability in the deletion breakpoints, FISH studies showed false-negative results in 10, 40, and 28% of the samples tested for the IKZF1,PAX5, and CDKN2A/B gene deletions, respectively. The PAX5 and IKZF1 abnormalities are highly specific to B-ALL and can be used as diagnostic markers. Moreover, IKZF1 alterations frequently coexist with a BCR-ABL gene fusion. Our study revealed multiple additional B-ALL-specific genomic alterations and showed that aCGH is a more sensitive method than FISH, allowing whole genome profiling and identification of aberrations of diagnostic and prognostic significance in patients with B-ALL.

Background Infections are the leading cause of therapy‐related mortality in pediatric patients with acute myeloid leukemia (AML). Although effectiveness of levofloxacin antibacterial prophylaxis in oncology patients is recognized, its cost‐effectiveness is unknown. This study evaluated epidemiologic data regarding levofloxacin use and the cost‐effectiveness of this strategy as the cost per bacteremia episode, intensive care unit (ICU) admission, and death avoided in children with AML. Procedure A retrospective cohort study using the Pediatric Health Information System (PHIS) database compared demographic and clinical characteristics and receipt of levofloxacin prophylaxis in children with AML admitted for chemotherapy from January 1, 2014, through December 31, 2018. We then developed a decision analysis model in this population that compared costs associated with bacteremia, ICU admission, or death secondary to bacteremia to levofloxacin prophylaxis cost from a healthcare perspective. Time horizon is one chemotherapy cycle. Probabilistic and one‐way sensitivity analyses evaluated model uncertainty. Results Prophylaxis cost $8491 per bacteremia episode prevented compared with an average added hospital cost of $119 478. Prophylaxis cost $81 609 per ICU admission avoided, compared with an average added hospital cost of $94 181. Prophylaxis cost $220 457 per death avoided. In sensitivity analysis, at a willingness‐to‐pay threshold of $100 000 per bacteremia episode avoided, prophylaxis remained cost‐effective in 94.6% of simulations. Prophylaxis use was more common in recent years in patients with relapsed disease and with chemotherapy regimens considered more intensive. Conclusion Prophylaxis is cost‐effective in preventing bacterial infections in patients with AML. Findings support increased use in patients considered at high risk of bacterial infection secondary to myelosuppression.

OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic is an unprecedented event in modern medicine. In this study, we evaluate pediatric faculty and trainee attitudes and perspectives related to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and their roles in the COVID-19 pandemic. METHODS: We surveyed a pediatric hospital’s faculty and trainees (n = 701) in April 2020 about their concerns related to SARS-CoV-2, trust in current recommendations, and attitudes toward trainee roles. We used descriptive statistics to analyze results and compared across sex and roles using logistic regression. RESULTS: Among 320 respondents (46% response rate), 73% were concerned with personal risk of SARS-CoV-2 infection and 88% were concerned with loved ones’ risk. Twenty-four percent were concerned because of personal risk factors. Nearly half expressed concerns as their family’s major provider and about salary changes (48% and 46%). Seventy-nine percent were concerned about lack of personal protective equipment and 43% about redeployment. Respondents endorsed varying levels of trust in recommendations related to COVID-19. Nearly three-fourths (72%) felt trainees are essential personnel. The majority were receptive to returning to usual patient care and training as the pandemic progresses. Significant differences exist across sex and roles related to levels of concern, trust, and trainee roles. CONCLUSIONS: In this study, we assess the concerns and perspectives of pediatric faculty and trainees related to the COVID-19 pandemic. Most view trainees as essential personnel and recognize the importance of direct patient care in their training. These results can be used to inform policy changes and trainee roles as the COVID-19 pandemic progresses.

Intestinal transplantation is a successful treatment for children with intestinal failure, but has many potential complications. PTLD, a clinically and histologically diverse malignancy, occurs frequently after intestinal transplantation and can be fatal. The management of this disease is particularly challenging. The rejection-prone intestinal allograft requires high levels of immunosuppression, a precondition for PTLD. While EBV infection clearly plays a role in disease pathogenesis, the relatively naïve immune system of children is another likely contributor. As a result, pediatric intestine recipients have a higher risk of developing PTLD than other solid organ recipients. Other risk factors for disease development such as molecular and genomic changes that precipitate malignant transformation are not fully understood, especially among children. Studies on adults have started to describe the molecular pathogenesis of PTLD, but the genomic landscape of the malignancy remains largely undefined in pediatric intestinal transplant patients. In this review, we describe what is known about PTLD in pediatric patients after intestinal transplant and highlight current knowledge gaps to better direct future investigations in the pediatric population.